Azapentylene-diammonium compounds



Patented Feb. 9, 1954 UNITED STATES PATENT OFFICE AZAPENTYLENE-DIAIHMONIUM COMPOUNDS Karl Micscher, Riehen, and Adrian Marxer, Basel, Switzerland, assignors to Ciba Pharmaceutical Products, Inc., Summit, N. J.

No Drawing. Application December 9, 1952, Serial No. 325,023

Claims priority, application Switzerland January 29, 1952 4 Claims. (Cl. 260-567.6)

This invention relates to secondary 3-azapentylene (1:5) di trialkylammonium compounds of the formula The new compounds can be used for the manu-- facture of medicaments. By methylation in 3- position they can be converted into compounds having a good ganglionic blocking effect. Owing to their ganglionic blocking action the new compounds themselves can also be used as medicaments.

Especially valuable are compounds of the above formula in which at least Rl-R-i indicate methyl radicals, primarily N: NzN :N'-tetramethyl-N:N'- diethyl-3-azapenty1ene-and NzNzNzN' :N :N'- hexamethyl 3 azapentylene (1:5) diammonium compounds, more especially the N:N:- N:N-tetramethyl-N:N'-diethyl 3 azapentylene-(1:5)-diammonium dibromide of the formula CHzCHrlTKCHa): Br C2H5 and the N:N:N:N :N' :N'-hexamethyl-3-azapen tylene-(l :5) -diammonium diiodide of the formula CHzCHr-IGKCHOa I- HN CH2OH2N(OHa)s I- The specified quaternary ammonium com pounds are obtained when azalkane diamines of the formula are treated with quaternating agents which are capable of introducing an alkyl radical with 1-3 carbon atoms. As quaternating agents there are suitable especially, reactive esters of corresponding alcohols, for example alkyl halides, such as methyl or ethyl chloride, bromide or iodide, and also dialkyl sulfates, such as climethyl sulfate or diethyl sulfate or alkyl or aryl sulfonic acid esters, such as para-toluene sulfonic acid methyl ester. The reaction may be carried out with advantage in the presence of solvents such as alcohol or ace tone.

The quaternary ammonium salts can be converted in the customary manner into their quaternary ammonium hydroxides, for example by reaction of the halides with silver oxide, by reaction of the sulfates with barium hydroxide or by treatment with anion exchangers. From the bases thus obtained, by reaction with therapeutically applicable or non-toxic acids, the quaternary salts of such inorganic or organic acids can be produced, for example of hydrohalic acids, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid, alkylor arylsulfonic acid, acetic acid, propionic acid, succinic acid, tartaric acid, citric acid or benzoic acid. Moreover, the quaternary salts containing the free secondary amino group can be converted into therapeutically applicable or non-toxic acid addition salts, such as that of hydrohalic acids, by reaction with therapeutically applicable or non-toxic acids, especially strong inorganic acids. From these acid addition salts, there can be obtained, for example by treating them with an equivalent of caustic soda solution, the appropriate quaternary diammonium salts containing the free secondary amino group.

The following examples illustrate the invention, the relation between part by weight and part by volume being he same as that between gram and cubic centimeter:

Emample 1 15.9 parts by weight of w:w'-tetramethyl-diethylene triamine are dissolved in 150 parts by volume of absolute ethyl alcohol and the solution treated dropwise with 298 parts by weight of methyl iodide in 50 parts by volume of absolute ethyl alcohol. During the addition, the whole is cooled with water, finally being stirred in an oil bath at 90 C. for 5 hours. After a short time the deposition of crystals commences. These melt at 222-224" C. They consist of NzNzNzN' :N :N'- hexamethyl 3 azapentylene- (1:5) -diammonium diiodide of the formula CHzCHzI HCHah I- omcmii'uomp 1- By reacting N:N:N':N'-tetraethyl-diethylene triamine with methyl iodide in the manner described above, there is obtained N:N'-dimethyl- N:N:N :N'- tetraethyl- 3- azapentylene- (1:5)- diammonium diiodide of the formula which, after sintering at 200 C., melts at 207 C. By adding an excess of hydroiodic acid to the aqueous ethyl alcoholic solution of N:N:N:N' :N' :N'-hexamethyl-3-azapentylene- (1 :5) -di-ammonium diiodide,

evaporation to dryness under reduced pressure and treatment with ethanol, there is obtained the N :N:N:N' :N :N- hexamethyl- 3- aza-pentylene- (1:5) -diammonium diiodide-hydroiodide of the formula oHzoHifiwHap I- HLHN CHzCH2&(CH3)a I which melts at 184-187 C. and decomposes at Example 2 15.9 parts by weight of w:w-tetramethyl-diethylenetriamine are dissolved in 150 parts by volume of absolute ethyl alcohol and treated with 32.8 parts by weight of ethyl iodide in 50 parts by volume of absolute ethyl alcohol. After hours stirring in an oil bath at 90 C., the crystals formed are filtered with suction and washed with ethyl alcohol. Compact crystals of N N: N :N' -tetramethyl-N N -diethyl-3-azapentylene (1:5) -diammonium diiodide of melting 4 point 222-224 C. are obtained. They have the formula Example 3 31.8 parts by weight of w:w'-tetramethyl-diethylenetriamine are dissolved in 200 parts by volume of alcohol and 45.8 parts by weight of ethyl bromide in 50 parts by volume of alcohol are gradually added. The whole is stirred for 5 hours in an oil bath at C., the alcohol evaporated to a far-reaching extent under reduced pressure and after the addition of acetone there are obtained, after some time, crystals of meltin point 214-21'7 C. They consist of N:N :N' :N'- tetramethyl N:N diethyl 3 aza pentylene- (1 :5) -diammoniumdibromide of the formula CHzCHzlTKCHs): B1- 02115 By agitating for several hours an aqueous solution of N: N N :N-tetramethyl-N:N'-diethyl-3- azapentylene (1 :5) diammonium dibromide with a small excess of silver oxide there is obtained a solution of the strongly basic N:N:N':N'- tetramethyl NzN' diethyl 3 aza pentylene- (1 :5) -diammonium-dihydroxide in water. After the addition of the calculated quantity of 4N- hydrochloric acid to produce a neutral reaction the reaction mass is evaporated to dryness under reduced pressure. The residue is dissolved in a little absolute ethyl alcohol and the N:N:N:N- tetramethyl N:N' diethyl 3 aza pentylene- (1:5)diammonium-dioh1oride caused to crystallize by the addition of a small quantity of acetone or ethyl acetate. It forms deliquescent crystals.

By adding to the solution of N:N:N:N-tetramethyl- N:N- diethyl 3- aza-pentylene (1 :5) diammonium dihydroxide in water a double'equimolecular amount of tartaric acid, the corre sponding ditartrate of the formula is obtained in an analogous manner.

What is claimed is: 1. A member selected from the group consist.-

ing of a secondary 3-aza-penty1ene-(lz5)'diwherein Rl-Rfi represent alkyl radical with 1-3 1-3 carbon atoms and A- stands for a non-toxic carbon atoms and A- stands for a non-toxic anion.

anion, and a therapeutically applicable acid ad- 3. N:N:N:N tetramethyl N:N' diethyldition salt thereof. B-aza-pentylene- (1 :5) -diammonium-clibromide. 2. Acompound of the formula 5 4. N:N:N:N':N':N' hexamethyl 3 aza- CHS pentylene- (1: 5) -diammonium-diioclicle.

KARL IVIIESCHER. Q ADRIAN MARKER.

s H CBS 10 References Cited in the file of this patent QZ FOREIGN PATENTS Number Country Date 169,569 Austria Nov. 26, 1951 wherein R5 and R6 represent alkyl radicals with 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A SECONDARY 3-AZA-PENTYLENE-(1:5)-DITRIALKYLAMMONIUM COMPOUND OF THE FORMULA 